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The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide\/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide\u2010mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite\u2010mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite\u2010mediated increased permeability of the blood\u2013brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis\u2010driven MCS research.\u2014Pall, M. L. NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    16, 1407\u20131417 (2002)\n                  <\/jats:p>","DOI":"10.1096\/fj.01-0861hyp","type":"journal-article","created":{"date-parts":[[2002,8,30]],"date-time":"2002-08-30T19:03:10Z","timestamp":1030734190000},"page":"1407-1417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity"],"prefix":"10.1096","volume":"16","author":[{"given":"MARTIN L.","family":"PALL","sequence":"first","affiliation":[{"name":"School of Molecular Biosciences Washington State University  Pullman Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2002,9]]},"reference":[{"volume-title":"Chemical Exposures: Low Levels and High Stakes","year":"1998","author":"Ashford N. 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